Preparation of carboxylate and sulfonate salts of 1-cis-(3-chloro-2-propenyl)-3,5,7-triaza-1-azoniatricyclo(3.3.1.13,7)decane-II

ABSTRACT

Compounds of the .[.formulas.]. .Iadd.formula .Iaddend. ##STR1## wherein X -  is a lower alkyl carboxylate .[.(I).]., a phenylcarboxylate .[.(I).]., a lower alkylsulfonate .[.(II).]. or a phenylsulfonate .[.(II).]. anion, wherein the phenyl ring may have lower alkyl, lower alkoxy, hydroxyl, amino, nitro, bromo or chloro substitution. The compounds are prepared by reacting the .[.carbinolamine.]. .Iadd.ring-opened intermediate .Iaddend.prepared by reacting cis-1-(3-chloro-2-propenyl)-3,5,7-triaza-1-azoniatricyclo(3.3.1.1 3 ,7)decane chloride with aqueous sodium hydroxide, with a carboxylic or sulfonic acid, as indicated, to form the corresponding 1-cis-(3-chloro-2-propenyl)-3,5,7-triaza-1-azoniatricyclo(3.3.1.1 3 ,7)decane carboxylate or sulfonate. These compounds have antimicrobial activity.

BACKGROUND OF THE INVENTION

The compoundcis-1-(3-chloro-2-propenyl)-3,5,7-triaza-1-azoniatricyclo(3.3.1.1³,7)decanechloride, known commercially as Dowicil 200 antimicrobial, is describedin U.S. Pat. No. 3,228,829. Dowicil 200 antimicrobial possesses inherentinstability problems. Also, various salts of the N-methyl analog ofDowicil 200 are known, i.e., the nitrate, chlorate, sulfate, rhodanide,metaborate, bichromate, perchlorate, ferrocyanate and picrate; U.S. Pat.No. 1,336,709. No utility is claimed for these latter compounds,however.

SUMMARY OF THE INVENTION

This invention concerns mono- .[.and di-salts.]. .Iadd.salts.Iaddend.corresponding to the .[.formula.]. .Iadd.formula .Iaddend.##STR2## wherein X⁻ represents a lower alkyl carboxylate, .[.(I).]. aphenylcarboxylate .[.(I).]. a lower alkyl sulfonate .[.(II).]. or aphenylsulfonate .[.(II).]. anion wherein the phenyl ring may have loweralkyl, lower alkoxy, hydroxyl, amino, nitro, bromo or chlorosubstitution, hereinafter designated "a phenyl" or "a benzene." In thespecification and claims, "lower alkyl" and "lower alkoxy" designate a 1to 4 carbon atom alkyl or alkoxy group, respectively.

The compounds are prepared by reacting Dowicil 200 brand ofcis-1-(3-chloro-2-propenyl)-3,5,7-triaza-1-azoniatricyclo(3.3.1.1³,7)decanechloride, sometimes also referred to herein as "Cis," with excessaqueous sodium hydroxide at room temperature to give .[.thecarbinolamine,.]. .Iadd.a ring-opened, isolatable basic intermediate,.Iaddend..[.7-cis-(3-chloro-2-propenyl)-1,3,5,7-tetraazabicyclo(3.3.1)-nonane-3-methanol,.].hereinafter referred to as .[."Carbinolamine,".]. .Iadd."basic oil"..Iaddend..[.according to the following reaction scheme:.]. ##STR3## The.[.Carbinolamine.]. .Iadd.basic oil .Iaddend.is recovered from thereaction medium by extraction with an inert neutral organic solvent suchas ether or benzene, the extract is dried over sodium sulfate and thesolvent is evaporated to give the .[.Carbinolamine.]. .Iadd.basic oil.Iaddend.as a viscous oil.

The mono- .[.and .[.di-salts.]. .Iadd.salts .Iaddend.of the.[.Carbinolamine.]. .Iadd.basic oil .Iaddend.are prepared by addingsubstantially one molar proportion of the .Iadd.corresponding.Iaddend.sulfonic acid .[.or two molar proportions of the carboxylicacid, respectively,.]. in solution in an inert, neutral organic solvent,e.g., acetone, ether or benzene, to substantially one molar proportionof the .[.Carbinolamine.]. .Iadd.basic oil .Iaddend.dissolved in asimilar inert, neutral organic solvent. Upon stirring the reactionmixture at room temperature, a copious white precipitate forms which iseasily isolated by filtration. It is dried to .Iadd.give a crude.Iaddend.yield .[.a pure white.]. .Iadd.of .Iaddend.mono- .[.or.[.di-salt.]. .Iadd.salt. .Iaddend.The structure is confirmed byelemental analysis and by N.M.R.

The following procedures and examples further describe the invention andthe manner and process of making and using it so as to enable the artskilled to make and use the invention, and set forth the best modecontemplated by the inventors of carrying out the invention.

EXAMPLE 1 Preparation of the .[.Di-benzoate.]..Iadd.Mono-benzoate.Iaddend. Salt of Cis

A quantity of 80 g. (2.0 mole) NaOH was dissolved in 500 ml. H₂ O andcooled to room temperature. 100 Grams (0.4 mole) of Cis was added slowlyto the caustic solution and the reaction mixture was stirred 15 minutesat ambient temperature. Product .[.Carbinolamine.]. .Iadd.basic oil.Iaddend.was extracted with benzene, dried over Na₂ SO₄ and the benzeneevaporated to give 72 g. (78% yield) of a viscous oil, the.[.Carbinolamine.]. .Iadd.basic oil. .Iaddend.

10.0 Grams (0.043 mole) .[.Carbinolamine.]. .Iadd.basic oil .Iaddend.wasdissolved in 50 ml. of ether, then filtered through Celite to give aclear, amber solution. 10.62 Grams (0.087 mole) benzoic acid in 100 ml.ether was added to the .[.Carbinolamine.]. .Iadd.basic oil.Iaddend.solution at room temperature with stirring. In seconds, acopious white precipitate formed which was easily isolated byfiltration, followed by drying to yield 18.0 g. (92% yield) of .[.purewhite Cis dibenzoate.]. .Iadd.mono-benzoate.Iaddend., m.p. 70°-72° C.Elemental analysis and N.M.R indicated the .[.bis-salt.]..Iadd.mono-salt .Iaddend.had been prepared.

EXAMPLE 2 Preparation of the p-Toluene Sulfonate Mono-Salt of Cis

A quantity of 5.28 g. (0.021 mole) .[.Carbinolamine.]. .Iadd.basic oil.Iaddend.was dissolved in 50 ml. cold ether, then filtered throughCelite to give a clear solution. 4.08 Grams (0.021 mole) p-toluenesulfonic acid was dissolved in 100 ml. ether, then added to the cold.[.Carbinolamine.]. .Iadd.basic oil .Iaddend.solution (0° C.). A whitecrystalline precipitate formed immediately. After filtration and drying,the yield was 4 g. (ca. 50%), m.p. 125.5°127° C. N.M.R. and elementalanalysis indicated the titular product was prepared.

The following compounds .[.Ia-Ii.]. .Iadd.Ia-Ij .Iaddend. .[.and IIa.].were prepared by substituting the corresponding carboxylic or sulfonicacid in the procedure of Example 1 or Example 2 to obtain the indicated.[.di- or.]. mono-salt..[., respectively.].

    __________________________________________________________________________    .[.                                                                           .].STR4##           .Iadd.                                                                        .Iaddend.                                                 .[.(I).].           .[.(II).].                                                __________________________________________________________________________               .Iadd.X.Iaddend.                                                                              m.p. ° C.                                   __________________________________________________________________________            .[.Ia. ortho-HOC.sub.6 H.sub.4 COO.].                                                            .[.95-97.].                                                 .Iadd.Ia. ortho-OHC.sub.6 H.sub.4 COO.Iaddend.                                                   .Iadd.95-97.Iaddend.                                       Ib. .[.P.]..Iadd.p.Iaddend. ara-HOC.sub.6 H.sub.4 COO                                            65-67                                                      Ic. para-CH.sub.3 C.sub.6 H.sub.4 COO                                                            87-89                                                      Id. ortho-NH.sub.2 C.sub.6 H.sub.4 COO                                                           66-67                                                      Ie. ortho-NO.sub.2 C.sub.6 H.sub.4 COO                                                           97-99                                                      If. para-ClC.sub.6 H.sub.4 COO                                                                   96-96.5                                                    Ig. 2,4-Cl.sub.2 C.sub.6 H.sub.3 COO                                                             98-100                                                     Ih. ortho-BrC.sub.6 H.sub.4 COO                                                                  40                                                         Ii. CH.sub.3 COO   25                                                         .Iadd.Ij. .Iaddend. .[.IIa. .].CH.sub.3 SO.sub.3                                                 120-121                                           __________________________________________________________________________

The Compounds of the invention are useful as antimicrobials for thecontrol of bacteria and fungi. This is not to suggest that the Compoundsand their mixtures are equally effective against all such organisms atthe same concentration. For such uses the Compounds or their mixturescan be employed in an unmodified form or dispersed on a finely dividedsolid and employed as dusts. Such mixtures can also be dispersed inwater with the aid of a surface-active agent and the resulting emulsionsemployed as sprays. In other procedures, the products can be employed asactive constituents in solvent solutions, oil-in-water or water-in-oilemulsions, including cosmetic emulsions. The augmented compositions areadapted to be formulated as concentrates and subsequently diluted withadditional liquid or solid adjuvant to produce the ultimate treatingcompositions. Good results are obtained when employing compositionscontaining antimicrobial concentrations from about 100 or about 1,000parts by weight of one or more of the compounds per million parts ofsuch compositions.

Incorporation of the compounds of this invention into materials whichare subject to bacterial and/or fungal attack inhibits the growth ofsuch microbes and preserves the original value of the materials. Thecompounds are sufficiently nonvolatile and water-insoluble that theywill persist on or in such materials for long periods of time. Examplesof materials which are adversely effected by fungal growth are latex andalkyd paint films, wood and wooden products. The inventive compounds aresufficiently active against fungi that only small quantities arerequired to prevent mildew on paint films or wood rot. The compounds aretherefore useful for long-term protection against fungal growth in or onmaterials having a wood basis or a protective or decorative paint filmsubject to fungal attack.

In representative operations, the products of the invention when testedfor antimicrobial activity using conventional agar dilution tests gavecomplete growth inhibition against the following organisms at theindicated concentrations in parts per million:

    __________________________________________________________________________    Minimum Inhibitory Concentration, ppm                                         __________________________________________________________________________    Compound                                                                      of                                                                            Example                                                                             Sa  St  Aa  Pa  Cp   Sc   An  Pen                                       __________________________________________________________________________    1     100 50  100 250 >500 >500 >500                                                                              500                                       2     250 50  100 250 ± ± >500                                                                              500                                       Ia    100 50  100 250 ± ± >500                                                                              >500                                      Ib     75 50   75 250 ∓ ± >500                                                                              500                                       Ic    100 100 100 250 ± 500  >500                                                                              500                                       Id    250 50  250 250 ∓ 500  >500                                                                              500                                       Ie     75 25  250 250 >500 >500 >500                                                                              >500                                      If    250 75  250 250 250  500   250                                                                              100                                       Ig     50 50  250 250 >500 >500 >500                                                                              ∓                                      Ih    250 75  250 250 >500 >500 >500                                                                              >500                                      Ii    250 50  250 250 250  500   500                                                                              100                                       .Iadd. Ij.Iaddend..[.IIa..].                                                        250 75   75 250 500  500   500                                                                              250                                       Cis*   50 25   50 100 ± 250  >500                                                                              250                                       __________________________________________________________________________     *Dowicil○ .sup.R  200 antimicrobial                                    Sa = S. aureus                                                                St = S. typhosa                                                               Aa = A. aerogenes                                                             Pa = P. aeruginosa                                                            Cp = C. pelliculosa                                                           Sc = S. cerevisiae                                                            An = A. niger                                                                 Pen = P. chrysogenum                                                          ± = 50% inhibition at 500 ppm                                              ∓ = >90% inhibition at 500 ppm                                        

What is claimed is:
 1. A compound corresponding to .[.one of.]. the.[.formulas.]. .Iadd.formula .Iaddend. ##STR6## wherein X represents alower alkyl carboxylate, .[.(I).]. a lower alkyl sulfonate, .[.(II).]. abenzoate .[.(I).]. or a phenylsulfonate .[.(II).]. salt wherein thephenyl group may contain lower alkyl, lower alkoxy, hydroxyl, amino,nitro, chloro or bromo substitution.
 2. The compound of claim 1represented by formula (I) wherein X⁻ represents the benzoate anion. 3.The compound of claim 1 represented by formula .[.(II).]. .Iadd.(I).Iaddend.wherein X⁻ represents the p-toluene sulfonate anion.
 4. Thecompound of claim 1 represented by formula (I) wherein X⁻ represents theo-hydroxy benzoate anion.
 5. The compound of claim 1 represented byformula (I) wherein X⁻ represents the p-hydroxybenzoate anion.
 6. Thecompound of claim 1 represented by formula (I) wherein X⁻ represents thep-methylbenzoate anion.
 7. The compound of claim 1 represented byformula (I) wherein X⁻ represents the o-aminobenzoate anion.
 8. Thecompound of claim 1 represented by formula (I) wherein X⁻ represents theo-nitrobenzoate anion.
 9. The compound of claim 1 represented by formula(I) wherein X⁻ represents the p-chlorobenzoate anion.
 10. The compoundof claim 1 represented by formula (I) wherein X⁻ represents the2,4-dichlorobenzoate anion.
 11. The compound of claim 1 represented byformula (I) wherein X⁻ represents the o-bromobenzoate anion.
 12. Thecompound of claim 1 represented by formula (I) wherein X⁻ represents theacetate anion.
 13. The compound of claim 1 represented by formula.[.(II).]. .Iadd.(I) .Iaddend.wherein X⁻ represents the methyl sulfonateanion.
 14. Method for making a carboxylate or a sulfonate salt ofcis-1-(3-chloro-2-propenyl)-3,5,7-triaza-1-azoniatricyclo(3.3.1.1³,7)decanewhich comprises adding to an inert, neutral organic solvent solution of.[.7cis-(3-chloro-2-propenyl)-1,3,5,7-tetraazabicyclo-(3.3.1)-nonane-3-methanol.]..Iadd.the reaction product of Dowicil-200 with excess aqueous sodiumhydroxide .Iaddend.at a temperature between about 0° C. and roomtemperature (a) substantially two molar proportions of a lower alkylcarboxylic acid, or a benzoic acid having lower alkyl, lower alkoxy,hydroxyl, amino, nitro, chloro or bromo substitution, or (b)substantially one molar proportion of a lower alkyl sulfonic acid or abenzene sulfonic acid, respectively, in an inert, neutral organicsolvent and recovering the said product from the reaction medium.